OCTA measurements in Behcet’s disease across different stages of the disease activity: A systematic review and meta-analysis

Mehrdad Mozafar; Mobina Amanollahi; Reza Samiee; Melika Jameie; Ali Mousavi; Zahra Ghanbari; Helia Nafar; Negar Mozafar; Fatemeh Amiri; Mehdi Azizmohammad Looha; Elias Khalili Pour; Nazanin Ebrahimiadib

doi:10.1371/journal.pone.0323192

Peer Review History

Original SubmissionOctober 17, 2024
Decision Letter - Ayman Elnahry, Editor Dear Dr. Khalili Pour, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Mar 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Ayman Elnahry Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In this instance it seems there may be acceptable restrictions in place that prevent the public sharing of your minimal data. However, in line with our goal of ensuring long-term data availability to all interested researchers, PLOS’ Data Policy states that authors cannot be the sole named individuals responsible for ensuring data access (http://journals.plos.org/plosone/s/data-availability#loc-acceptable-data-sharing-methods). Data requests to a non-author institutional point of contact, such as a data access or ethics committee, helps guarantee long term stability and availability of data. Providing interested researchers with a durable point of contact ensures data will be accessible even if an author changes email addresses, institutions, or becomes unavailable to answer requests. Before we proceed with your manuscript, please also provide non-author contact information (phone/email/hyperlink) for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If no institutional body is available to respond to requests for your minimal data, please consider if there any institutional representatives who did not collaborate in the study, and are not listed as authors on the manuscript, who would be able to hold the data and respond to external requests for data access? If so, please provide their contact information (i.e., email address). Please also provide details on how you will ensure persistent or long-term data storage and availability. 3. Please include a caption for figure 9. 4. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following: A numbered table of all studies identified in the literature search, including those that were excluded from the analyses. For every excluded study, the table should list the reason(s) for exclusion. If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed. A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study: Name of data extractors and date of data extraction Confirmation that the study was eligible to be included in the review. All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses. If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group. If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome. An explanation of how missing data were handled. This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected. Additional Editor Comments: The authors report an extensive systematic review and meta analysis of studies that assessed different groups with BD using OCTA. The analysis is extensive and comprehensive and the authors should be congratulated on this. The main issue is the multiple comparisons that the authors underwent due to the heterogeneity of the studies. The authors should therefore perform p-value corrections for their analyses such as Bonferroni correction. When conducting a statistical analysis that involves multiple comparisons, such as comparing multiple subgroups, the Bonferroni correction can be applied to reduce the risk of false positives. I recommend the authors do this correction to all their analyses including comparisons and meta analyses results. The authors should revise the discussion section accordingly as needed. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Very interesting study with sound methodology and statistics. Nice effort. My only comment would be that the conclusion could be more precise and reflecting the results. For example, the suggestion of screening eyes with non ocular Behcet’s lacks the correlation to management as screening will only be relevant if a particular intervention would be undertaken. Reviewer #2: Line 74 and line 128 any disagreements were solved by SHOULD be any disagreement was solved by Page 16 at the end senile SHOULD age-related macular degeneration Page 17 top line glaucoma suspicion SHOULD be glaucoma suspect Page 17 bottom. Dense media obstacles SHOULD be Dense media opacity CONCLUSION: “Given that our analysis found no significant reduction in vessel density in cases of active BD” Reason: patients on prior medical therapy but with flare up; degree of activity varies from mild to severe with mild not affecting vessel density and severe causing temporary occlusion; view too bad to allow visualization of vessels in severe uveitis precluding good quality OCTA (selection bias). Retinal vascular occlusions were found in a third of ocular BD patients. Ostrovsky M, Ramon D, Iriqat S, Shteiwi A, Sharon Y, Kramer M, Vishnevskia-Dai V, Sar S, Boulos Y, Tomkins-Netzer O, Lavee N, Ben-Arie-Weintrob Y, Pizem H, Hareuveni-Blum T, Schneck M, Gepstein R, Masarwa D, Nakhoul N, Bakshi E, Shulman S, Goldstein M, Anouk M, Rosenblatt A, Habot-Wilner Z. Retinal vascular occlusions in ocular Behçet disease - a comparative analysis. Acta Ophthalmol. 2023 Sep;101(6):619-626. Population bias: Risk factors for retinal vascular occlusions included Jewish ethnicity (p < 0.05). Ostrovsky M, Ramon D, Iriqat S, Shteiwi A, Sharon Y, Kramer M, Vishnevskia-Dai V, Sar S, Boulos Y, Tomkins-Netzer O, Lavee N, Ben-Arie-Weintrob Y, Pizem H, Hareuveni-Blum T, Schneck M, Gepstein R, Masarwa D, Nakhoul N, Bakshi E, Shulman S, Goldstein M, Anouk M, Rosenblatt A, Habot-Wilner Z. Retinal vascular occlusions in ocular Behçet disease - a comparative analysis. Acta Ophthalmol. 2023 Sep;101(6):619-626. Yahia, Salim Ben, Rim Kahloun, Bechir Jelliti, and Moncef Khairallah. 2011. “Branch Retinal Artery Occlusion Associated with Behçet Disease.” Ocular Immunology and Inflammation 19 (4): 293–95. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: Yes: Amr Wassef Reviewer #2: Yes: Ahmad M Mansour ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0323192.r001
Revision 1
6 Mar 2025 Author Response PONE-D-24-46800 OCTA measurements in Behcet’s disease across different stages of the disease activity: A systematic review and meta-analysis PLOS ONE Reply: Dear Dr. Elnahry, Thank you very much for providing us with the opportunity to strengthen our manuscript. Having carefully considered the comments and suggestions, we have made all the relevant changes to our manuscript as outlined below in an itemized, point-by-point manner. We sincerely hope that these changes meet the approval criteria of the esteemed reviewers and the editorial board. Best Regards, Elias Khalili Pour M.D, Retina ward, Farabi Eye Hospital, South Kargar Street, Qazvin Square, Tehran, Iran. ekhalilipour@gmail.com ==========================================================================Response to the comments of the Journal Requirement: Dear Authors, You have done a large amount of work, which I appreciate. Some issues need to be improved. Comment #1: Please include a caption for figure 9. Reply: Thank you so much for bringing this to our attention. It is added now. ==========================================================================Response to the comments of the Esteemed Associate Editor: Comment #1: The authors report an extensive systematic review and meta analysis of studies that assessed different groups with BD using OCTA. The analysis is extensive and comprehensive and the authors should be congratulated on this. The main issue is the multiple comparisons that the authors underwent due to the heterogeneity of the studies. The authors should therefore perform p-value corrections for their analyses such as Bonferroni correction. When conducting a statistical analysis that involves multiple comparisons, such as comparing multiple subgroups, the Bonferroni correction can be applied to reduce the risk of false positives. I recommend the authors do this correction to all their analyses including comparisons and meta analyses results. The authors should revise the discussion section accordingly as needed. Response: We sincerely appreciate your thoughtful feedback and your recognition of the comprehensiveness of our systematic review and meta-analysis. Your suggestion regarding multiple comparisons and the application of p-value corrections is highly valuable, and we have carefully addressed this concern in our revised analysis. Implementation of Multiple Comparison Correction To account for the increased risk of false positives due to multiple comparisons, we applied the False Discovery Rate (FDR) correction using the Benjamini-Hochberg (BH) method rather than the Bonferroni correction. FDR correction is more appropriate for meta-analyses because it controls the expected proportion of false discoveries rather than strictly limiting Type I errors, which can be overly conservative in large-scale analyses. The Benjamini-Hochberg procedure follows these steps: Rank all p-values from smallest to largest across the multiple comparisons being made. Calculate the critical value for each p-value using the formula: α_(adjusted,i)= i/m×α where: i is the rank of the p-value, m is the total number of comparisons, and α is the desired false discovery rate (typically set at 0.05). Compare each p-value to its corresponding critical value. The largest p-value that is still below its critical value is considered significant, and all smaller p-values are also deemed significant. Adjust the p-values accordingly to ensure that they are monotonically increasing, preserving the correct ordering. Additionally, we implemented the FDR correction using R, applying the p.adjust() function with the Benjamini-Hochberg method, as follows: ---- # Example list of uncorrected p-values from our meta-analysis p_values <- c(0.045, 0.009, 0.021, 0.031, 0.002, 0.056, 0.015) # Apply Benjamini-Hochberg (FDR) correction adjusted_p_values <- p.adjust(p_values, method = "BH") # Print results data.frame(Uncorrected_P = p_values, Adjusted_P = adjusted_p_values) ---- Application of Correction to Results We have systematically re-evaluated all statistical comparisons and updated the p-values in our results accordingly. Specifically: All p-values from subgroup comparisons and meta-analyses have been adjusted using the Benjamini-Hochberg correction. We have carefully updated the results and p-values, ensuring that both raw and corrected values are now included in the manuscript. Notably, none of the previously significant raw p-values lost their significance after correction. Therefore, the discussion and main text of the results remain unchanged in this regard. A statement has been added to the method section, mentioning our approach for correcting for multiple comparisons. A new table (Table 4) has been added to the manuscript, where we now report the meta-analyses results along with both the uncorrected p-values and the corrected p-values for each comparison across all outcomes. This provides clarity on how the adjustments impact statistical significance and ensures full transparency in our methodology. Thank you once again for your constructive feedback, which has significantly improved our manuscript. ===========================================================================Response to the comments of the Reviewer 1: Comment #2: Very interesting study with sound methodology and statistics. Nice effort. My only comment would be that the conclusion could be more precise and reflecting the results. For example, the suggestion of screening eyes with non ocular Behcet’s lacks the correlation to management as screening will only be relevant if a particular intervention would be undertaken. Reply: Thank you for your thoughtful feedback and for recognizing the strengths of our study. We appreciate your suggestion regarding the precision of the conclusion, particularly in relation to the recommendation for screening eyes in patients with non-ocular Behçet’s disease (BD). We acknowledge that screening is most impactful when it directly informs management decisions. Our intention was to highlight the presence of retinal microvascular changes in non-ocular BD, as observed in OCTA studies, which may indicate subclinical vascular involvement. However, we agree that the clinical implications of such findings require further clarification. To address this, we have refined our conclusion to ensure it accurately reflects the results while acknowledging the need for additional research to determine the potential utility of retinal screening in clinical decision-making. ========================================================================== Response to the comments of the Reviewer 2: Comment #1: Line 74 and line 128 any disagreements were solved by SHOULD be any disagreement was solved by. Reply: Thank you very much for your precious comment. They are corrected grammatically. Comment #2: Page 16 at the end senile SHOULD age-related macular degeneration Reply: Thank you very much for your feedback. It is revised. Comment #3: Page 17 top line glaucoma suspicion SHOULD be glaucoma suspect. Reply: Thank you very much. We have changed the wording to “suspect”. Comment #4: Page 17 bottom. Dense media obstacles SHOULD be Dense media opacity. Reply: Thank you very much. We have changed the wording to “Dense media opacity”. ========================================================================= Comment #5: CONCLUSION: “Given that our analysis found no significant reduction in vessel density in cases of active BD” Reason: patients on prior medical therapy but with flare up; degree of activity varies from mild to severe with mild not affecting vessel density and severe causing temporary occlusion; view too bad to allow visualization of vessels in severe uveitis precluding good quality OCTA (selection bias). Retinal vascular occlusions were found in a third of ocular BD patients. Ostrovsky M, Ramon D, Iriqat S, Shteiwi A, Sharon Y, Kramer M, Vishnevskia-Dai V, Sar S, Boulos Y, Tomkins-Netzer O, Lavee N, Ben-Arie-Weintrob Y, Pizem H, Hareuveni-Blum T, Schneck M, Gepstein R, Masarwa D, Nakhoul N, Bakshi E, Shulman S, Goldstein M, Anouk M, Rosenblatt A, Habot-Wilner Z. Retinal vascular occlusions in ocular Behçet disease - a comparative analysis. Acta Ophthalmol. 2023 Sep;101(6):619-626. Population bias: Risk factors for retinal vascular occlusions included Jewish ethnicity (p < 0.05). Ostrovsky M, Ramon D, Iriqat S, Shteiwi A, Sharon Y, Kramer M, Vishnevskia-Dai V, Sar S, Boulos Y, Tomkins-Netzer O, Lavee N, Ben-Arie-Weintrob Y, Pizem H, Hareuveni-Blum T, Schneck M, Gepstein R, Masarwa D, Nakhoul N, Bakshi E, Shulman S, Goldstein M, Anouk M, Rosenblatt A, Habot-Wilner Z. Retinal vascular occlusions in ocular Behçet disease - a comparative analysis. Acta Ophthalmol. 2023 Sep;101(6):619-626. Yahia, Salim Ben, Rim Kahloun, Bechir Jelliti, and Moncef Khairallah. 2011. “Branch Retinal Artery Occlusion Associated with Behçet Disease.” Ocular Immunology and Inflammation 19 (4): 293–95. Reply: We appreciate the reviewer’s insightful observations regarding the potential reasons for the lack of significant reduction in vessel density in cases of active BD. In the limitation section of the discussion, we acknowledged that prior medical therapy, varying degrees of disease activity, and selection bias due to poor visualization in severe uveitis may have influenced the findings. Additionally, the presence of retinal vascular occlusions in a subset of BD patients could contribute to the heterogeneity of vascular changes observed in OCTA studies. To address these points, we have also revised the conclusion to better reflect these considerations and acknowledge the need for future studies to account for these confounding factors. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0323192.r002
Decision Letter - Ayman Elnahry, Editor <p>OCTA measurements in Behcet’s disease across different stages of the disease activity: A systematic review and meta-analysis PONE-D-24-46800R1 Dear Dr. Khalili Pour, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Ayman Elnahry Academic Editor PLOS ONE Additional Editor Comments (optional): Thank you for performing the necessary revisions. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: Yes ****** Reviewer #2: the revision addressed the reviewers comment and incorporated them in the text. I have no further notes to add and I congratulate the authors for this colossal work and for their innovative ideas ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #2: Yes: Ahmad Mansour ******** https://doi.org/10.1371/journal.pone.0323192.r003
Formally Accepted
Acceptance Letter - Ayman Elnahry, Editor PONE-D-24-46800R1 PLOS ONE Dear Dr. Khalili Pour, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Ayman Elnahry Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0323192.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .